Taste-masked pharmaceutical compositions with gastrosoluble pore-formers

ABSTRACT

There is provided a method for preparing an orally disintegrating tablet (ODT) composition comprising microparticles of one or more taste-masked active pharmaceutical ingredient(s), rapidly-dispersing microgranules, and other optional, pharmaceutically acceptable excipients wherein the ODT disintegrates on contact with saliva in the buccal cavity forming a smooth, easy-to-swallow suspension. Furthermore, the microparticles (crystals, granules, beads or pellets containing the active), coated with a taste-masking membrane comprising a water-insoluble polymer and one or more gastrosoluble inorganic or organic pore-formers (practically insoluble in water and saliva, but soluble in an acidic buffer), exhibit acceptable taste-masking when placed in the oral cavity and provide rapid, substantially-complete release of the dose on entry into the stomach.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional. Application No.60/621,144, filed Oct. 21, 2004, which is hereby incorporated byreference.

TECHNICAL FIELD

This invention relates to an orally disintegrating tablet (ODT)composition comprising taste-masked microparticles of one or more activepharmaceutical ingredients suitable for oral administration for thetreatment of diseases and rapidly-dispersing microgranules comprising adisintegrant and a sugar alcohol or a saccharide, or a mixture thereof,each of which having an average particle diameter of not more than 30μm. The multi-particulate ODT composition contains rapidly-dispersingmicrogranules and drug-containing core particles (crystals or granules,beads or pellets of one or more active pharmaceutical ingredients)coated with a taste-masking membrane comprising a water-insolublepolymer in combination with one or more pore-formers such as inorganicor organic salts which are practically insoluble in water and saliva,but soluble in an acidic buffer. The multi-particulate ODT compositionrapidly disintegrates on contact with saliva when placed in the oralcavity forming a smooth, easy-to-swallow suspension containing coatedparticles exhibiting acceptable taste-masking and provides rapid,substantially-complete release of the dose on entry into the stomach,thereby enhancing the probability of achieving bioequivalence to thereference immediate-release (IR) product. The invention additionallyprovides a method of manufacturing orally disintegrating tabletscomprising rapidly-dispersing microgranules and acceptably taste-maskedmicroparticles (crystals, pellets, granules, or beads containing thedrug) with an average particle size of not more than about 400 μm, moreparticularly not more than about 300 μm, to provide a smooth mouthfeelleaving no aftertaste (non-gritty or non-chalky taste) after swallowingthe suspension.

BACKGROUND OF THE INVENTION

There are two types of most widely used dosage forms for medication byoral administration: tablets and capsules. However, such dosage formshave several disadvantages. For example, it is estimated that 50% of thepopulation have problems swallowing tablets (see Seager in Journal ofPharmacol. and Pharm. 50, pages 375-382, 1998); especially it is hardfor aged persons to swallow tablets or capsules or to medicate childrenwho are unable or unwilling to swallow tablets or capsules. This leadsto poor, even non-compliance with the treatment and thus has a negativeimpact on the efficacy of the treatment. The bitter taste of manyactives precludes the medication from being easily sprinkled onto foodsuch as applesauce, a commonly used method of administering medicationsto children. The conventional capsule or tablet dosage form is alsoinconvenient for the ‘people on the move’ who often do not have accessto drinking water or fluids. Chewable tablets comprising taste-maskedparticles capable of being chewed without experiencing a bitter tastewere introduced not too long ago, and these tablets became popular withchildren.

The bitter drug-containing cores incorporated into chewable tablets havethick coatings of mostly water-insoluble polymers such as ethylcelluloseto resist fracture during tablet compression and/or during chewing andconcomitant leakage of the bitter active. Consequently, substantiallycomplete release of the drug from such chewable tablets in thegastrointestinal tract takes 2 hours or longer. More recently, orallydisintegrating tablet (ODT) dosage forms have been introduced, whichrapidly dissolve or disintegrate in the buccal cavity and hence can betaken without water. Such medicines are convenient for all, the agedpersons, the children or the ‘people on the move’.

An ideal orally disintegrating tablet formulation comprisingrapidly-dispersing microgranules and drug-containing microparticles(crystals, pellets, granules, or beads containing the drug) with ataste-masking membrane (if required) should rapidly disintegrate oncontact with saliva in the oral cavity forming a smooth, easy-to-swallowsuspension containing taste-masked drug particles having an averageparticle diameter of not more than about 400 μm to provide a smoothmouthfeel leaving no aftertaste (i.e., little or minimal drug releasewith a non-gritty or non-chalky taste) until swallowed, and shouldprovide rapid, substantially-complete release upon arrival in thestomach in order to be bioequivalent to the reference product.

As indicated earlier, most of the active pharmaceutical ingredients inthe market are bitter to a varying degree. Typically, toeliminate/minimize drug-release in the oral cavity, the bitter drugsubstance was taste-masked in the prior art by providing a thickpolymer-membrane around the drug particle typically bymicroencapsulation (coacervation by phase separation) or fluid-bedcoating for preparing immediate release dosage forms (chewable tablets,sprinkles, sachets, suspensions). However, coating with water-insolublepolymers such as ethylcellulose (EC), cellulose acetate (CA), celluloseacetate phthalate, polyvinyl acetate, Eudragit® RS, RL, L, S and NE30Dpolymers, results in slower dissolution profiles andnot-too-infrequently results in imparting sustained-release properties.

Several marketed products, which are typically conventional oreffervescent based immediate-release dosage forms, exhibit a rapid-onsetof action with a T_(max) of about an hour or less. An undesirableconsequence of taste-masking using a water-insoluble polymer alone or incombination with a water-soluble polymer is in general the slowerrelease of the drug in the gastrointestinal tract. Eudragit E (EPO orE100), a copolymer consisting of dimethylaminoethyl methacrylate andneutral methacrylic acid esters with a weight-average molecular weightof 150,000 and a pK_(a) of 6.3, is soluble in gastric fluid below pH 5while it swells and/or is permeable in water and buffer solutions abovepH 5.0. The saliva is typically in the pH range of 6.7 to 7.4. Hence, itis likely that one achieves effective taste-masking in the oral cavity,although for very limited time, if the drug core is coated with EudragitE100/EPO alone or in combination with a water-soluble agent.

From a pharmaceutical and a practical point of view, the inventors ofthe present invention have examined various methods of taste-maskingbitter active pharmaceutical ingredients suitable for incorporation intoorally disintegrating tablets having the property of rapidlydisintegrating in the buccal cavity and leaving no aftertaste (goodcreamy mouthfeel) and additionally providing rapid,substantially-complete release of the dose in the stomach, therebyenhancing the probability of achieving bioequivalence to the referenceproduct. The method of producing taste-masked microparticles (meanparticle size of about 100-400 μm) in accordance with the presentinvention comprising one or more bitter active pharmaceuticalingredient(s) includes membrane-coating of drug-containing coreparticles (crystals, microgranules, drug-layered orextruded/spheronized-beads) with a mixture of a water-insoluble polymersuch as ethylcellulose or polyvinyl acetate and one or moregastrosoluble pore-former(s) such as inorganic or organic salts, at aratio of about 50/50 to 95/5 for a weight gain of not less than about 5%and not more than about 50% by weight, based on total weight of thecoated particle. These gastrosoluble pore-formers are insoluble in bothwater and saliva, but soluble in a gastric fluid (for example, calciumcarbonate or magnesium oxide). Furthermore, the microcapsules preparedin accordance with the present invention can be produced to exhibit thespecified criteria (viz., desired particle size distribution and littleor minimal release of the bitter active in the mouth (hence noaftertaste), and rapid-release of the dose from the taste-maskedmicroparticles upon entry into the stomach), to be suitable forincorporation into orally disintegrating tablets.

The taste-masking effectiveness is measured by % of the dose released ina simulated saliva fluid at a pH of 6.7-7.4. The smaller the % release,the more effective the taste-masking. A pharmaceutical composition withnot more than 10% of the dose released in about 3 minutes in a simulatedsaliva fluid (the longest anticipated residence time for taste-maskedmicroparticles in the mouth) is considered acceptably taste-masked. Onthe other hand, the drug release on oral administration is evaluated bymeasuring % of the dose released in an acidic pH of about 1.2. Thefaster the release of the drug from the taste-masked microparticles inthe stomach, the higher the probability of being bioequivalent to thereference product. A release of not less than about 60% of the dose inabout 30 minutes in the acidic buffer is considered acceptable forachieving bioequivalence to the reference product.

SUMMARY OF THE INVENTION

The present invention provides pharmaceutical compositions and methodsfor making taste-masked microparticles and orally disintegratingtablets. In accordance with particular embodiments, the compositionsprovide effective taste-masking, smooth mouthfeel (little or noaftertaste) and rapid/complete release upon reaching the stomach,thereby enhancing the probability of achieving bioequivalence to thereference product.

The multi-particulate compositions comprise taste-masked core particles(crystals or granules, beads or pellets comprising one or morebitter-tasting active pharmaceutical ingredient(s)) with a mixture of awater-insoluble polymer such as ethylcellulose and a gastrosolubleinorganic or organic pore-former such as calcium carbonate. Thetaste-masking membrane may be applied by fluid bed coating. Thetaste-masked composition prepared in accordance with the presentinvention rapidly releases the drug, i.e., not less, than about 60% ofthe dose released in 30 minutes, when tested for dissolution usingUnited States. Pharmacopoeia Apparatus 1 (baskets @100 rpm) or Apparatus2 (paddles @50 rpm) in 900 mL of 0.1N HCl, Another embodiment of theinvention relates to a pharmaceutical composition in the form of anorally disintegrating tablet comprising (i) rapidly-dispersingmicrogranules containing (a) a disintegrant and (b) a sugar alcohol, asaccharide or combination thereof whose average particle size is notmore than about 30 μm, (ii) microparticles of one or more bitter-tastingactive pharmaceutical ingredient(s) taste-masked with a polymer membranecomprising a blend of a water-insoluble polymer and a gastrosolubleinorganic or organic pore-former such calcium carbonate, and (iii)optionally other pharmaceutically acceptable excipients. In accordancewith particular embodiments, these orally disintegrating tablets havethe properties of disintegrating on contact with saliva in the buccalcavity in about 60 seconds forming a smooth easy-to-swallow suspensionwith no aftertaste (good creamy mouthfeel) and rapidly releasing thedose on entry into the stomach, thus enhancing the probability of beingbioequivalent to the reference product.

A taste-masked multiparticulate pharmaceutical composition comprising:

-   -   (a) a drug-containing core particle (crystal, granule, pellet,        bead and the like);    -   (b) a taste-masking membrane on said drug-containing core        particle comprising a combination of a water-insoluble polymer        and a gastrosoluble inorganic or organic pore-former at a ratio        ranging from about 95/5 to about 50/50 having a thickness of        from about 5% to about 50% based on the weight of the coated        particle and an average particle size of not more than about 400        μm is disclosed.

The composition typically exhibits acceptable taste-masking when thecomposition is placed in the oral cavity for 3 minutes, moreparticularly for 2 minutes, in some cases for 60 seconds, and inparticular until it is swallowed leaving little or no aftertaste (i.e.,experiencing no gritty or chalky taste) and the composition providesrapid, substantially-complete release of the dose upon entry into thestomach, i.e., releases not less than about 60% of the dose in 30 minwhen tested for dissolution using United States Pharmacopoeia Apparatus1 (Baskets® 100 rpm in 900 mL of pH 1.2 buffer).

A taste-masked multiparticulate pharmaceutical composition in the ODT(orally disintegrating tablet) form, which disintegrates on contact withsaliva in the buccal cavity in about 60 seconds forming a smootheasy-to-swallow suspension (no gritty or chalky aftertaste) is alsodisclosed. The ODT may comprise the drug-containing core particle(crystal, granule, pellet, bead and the like), with a taste-maskingmembrane on the drug-containing core particle. The taste-maskingmembrane may comprise a water-insoluble polymer and a gastrosolublepore-former at a ratio ranging from about 95/5 to about 50/50 having athickness of from about 5% to about 50% based on the weight of thecoated microparticle with an average particle size of not more thanabout 400 μm, or in some embodiments not more than about 300 μm. The ODTmay also include a rapidly-dispersing microgranule, with an averageparticle size of not more than about 300 μm, or in some embodiments notmore than about 200 μm, comprising a disintegrant and a sugar alcohol, asaccharide or a combination thereof, each having an average particlediameter of not more than about 30 μm, and optionally pharmaceuticallyacceptable excipients typically used in ODT formulations, viz., flavors,a sweetener, coloring agents, and other disintegrants.

The ODT in accordance with one embodiment exhibits the followingproperties:

-   -   1) disintegrates on contact with saliva in the oral cavity in        about 60 seconds forming a smooth, easy-to-swallow suspension        comprising taste-masked microparticles, and    -   2) taste-masked microparticles provide rapid,        substantially-complete release of the dose upon entry into the        stomach.

The ODT may comprise taste-masked microparticles demonstrating effectivetaste-masking by releasing not more than 10% in about 3 minutes (thelongest typical residence time anticipated for the ODT in the buccalcavity) when dissolution tested in a simulated saliva fluid (pH˜7.0)while releasing not less than 60% of the dose in about 30 minutes whendissolution tested in 0.1N HCl.

A method of manufacturing a taste-masked multi-particulate compositionwherein the dosage form comprises one or more active pharmaceuticalingredient(s) in sufficient quantities to be administered orally to apatient at prescribed dosing regimen to provide therapeutic efficacy isalso provided.

The taste-masked multiparticulate pharmaceutical composition may includeany pharmaceutically acceptable active ingredient requiringtaste-masking.

In accordance with particular embodiments, the method of preparing ataste-masked multi-particulate composition includes layering apharmaceutically acceptable drug from a polymeric binder solution ontoan inert particle selected from the group consisting of sugar spheresand cellulose spheres. Fluid bed or pan coating may be used to apply theactive and polymeric binder solution.

In accordance with certain embodiments, the core particles may becrystals with a desired particle size distribution, beads, microgranulesor pellets containing one or more active pharmaceutical ingredient(s),requiring taste-masking.

The taste-masked multiparticulate pharmaceutical composition may includea drug-containing core particle that is a drug-layered bead comprisingan inert particle such as a sugar sphere, a cellulose sphere or asilicon dioxide sphere coated with one or more pharmaceuticallyacceptable actives from a polymeric binder solution.

In accordance with certain embodiments, the drug-containing particle isa microgranule or an extruded/spheronized pellet comprising one or morepharmaceutically acceptable active ingredient(s), a polymeric binder,which imparts resilient characteristics to dried microgranules, ahydrophilic filler/diluent, and optionally a flavor, a sweetener and/ora disintegrant.

The microgranules of one or more active pharmaceutical ingredient(s) maybe prepared by a conventional high-shear or planetary granulationprocess or the pellets may be prepared by a conventionalgranulation-extrusion-spheronization process comprising an activepharmaceutical ingredient, a polymer binder and one or morefillers/diluents.

The water-insoluble polymer (e.g., ethylcellulose with an averageviscosity of 10 cps) and the gastrosoluble organic or inorganicpore-former (e.g., calcium carbonate or magnesium oxide) may be presentat a weight ratio of from about 95/5 to 50/50, more particularly fromabout 85/15 to 65/35 and the membrane thickness may vary from about 5%to 50%, more particularly from about 10% to 30% by weight in accordancewith particular embodiments.

In accordance with some embodiments of the present invention, thetaste-masked multiparticulate ODT formulation includesrapidly-dispersing microgranules at about 50% to about 90% by weight ofthe tablet comprising a disintegrant (e.g., crospovidone), and a sugaralcohol (e.g., mannitol) or a saccharide (e.g., lactose) or acombination thereof, each sugar alcohol or saccharide having an averageparticle diameter of not more than about 30 μm and a ratio of sugaralcohol or saccharide to disintegrant varying from about 90/10 to about99/1.

In accordance with particular embodiments of the present invention, therapidly-dispersing microgranules and taste-masked microparticles may bepresent in the ratio of about 6/1 to 2/1, more particularly from about4/1 to 3/1, to achieve a smooth mouth feel.

In accordance with certain embodiments of the present invention, amethod of manufacturing a taste-masked multi-particulate composition ofone or more active pharmaceutical ingredient(s) is also provided. Themethod may comprise the steps of:

-   -   a) preparing core particles (crystals with a particle size        distribution of 20-500 μm, more particularly of 30-300 μm,        beads, microgranules or pellets) of one or more active        pharmaceutical ingredient(s) as granules by a conventional        granulation process, as beads by drug-layering onto inert        particles from a polymeric binder solution in fluid-bed        equipment, or as microgranules or as pellets by a conventional        granulation of one or more active pharmaceutical ingredient(s),        one or more polymeric binder(s), a hydrophilic filler/diluent,        and optionally a flavor, a sweetener, and/or a disintegrant or        granulation-extrusion-spheronization process; and    -   b) coating core particles by applying a membrane comprising a        mixture (at a ratio of 95/5 to 50/50) of water-insoluble        ethylcellulose and gastrosoluble inorganic or organic        pore-former such as calcium carbonate, dissolved/dispersed in a        mixture of acetone and purified water, the membrane coating        comprising approximately from about 5% to about 50% based on the        total weight of the coated particles.

The composition may exhibit the following properties:

-   -   a) acceptable taste-masking when the composition is placed in        the oral cavity for 3 minutes, more particularly for 2 minutes        and in certain embodiments for 60 seconds, and in still other        embodiments, until it is swallowed leaving no aftertaste; and    -   b) rapid, substantially-complete release of the dose upon entry        into the stomach, i.e., releases not less than about 60% of the        dose in 30 min when tested for dissolution using United States        Pharmacopoeia Apparatus 1 (Baskets @100 rpm) or Apparatus 2        (paddles @50 rpm in 900 mL of pH 1.2 buffer).

In accordance with certain embodiments of the present invention, themethod comprises the steps of:

-   -   a) preparing core particles (crystals with a particle size        distribution of 20-500 μm, more particularly of 50-300 μm,        beads, microgranules, pellets) of one or more active        pharmaceutical ingredient(s) as described above;    -   b) taste-masking core particles by Applying a membrane        comprising a mixture of water-insoluble and gastrosoluble        inorganic or organic pore-former as described above, the        membrane coating comprising approximately about 5% to 50% based        on the total weight of the coated particles;    -   c) granulating a disintegrant such as Crospovidone with a sugar        alcohol or a saccharide, or a combination thereof, each having        an average particle diameter of not more than 30 μm, with water        or an alcohol-water mixture in a conventional granulator and        drying in a fluid bed equipment to produce granules with an        average particle size not more than 400 μm (more particularly        not more than 300 μm);    -   d) blending taste-masked microparticles of step (b) with rapidly        disintegrating microgranules of step (c) at a ratio of about ⅙        to about ½, and optionally other, pharmaceutically acceptable        ingredients, such as a flavoring agent (<0.5% w/w), a coloring        agent (<0.5% w/w), a sweetener (<0.5% w/w) and additional        disintegrant (up to 5% w/w); and    -   e) compressing into tablets using a conventional rotary tablet        press equipped with an external lubrication system to        pre-lubricate the dies and punches.

The ODT may exhibit the following properties:

-   -   1) disintegrates on contact with the saliva in the oral cavity        forming a smooth, easy-to-swallow suspension comprising        taste-masked microparticles,    -   2) leaves no aftertaste after swallowed (no gritty or chalky        mouthfeel),    -   3) provides rapid, substantially-complete release of the dose        upon entry into the stomach; or    -   4) the GDT when tested for dissolution using United States        Pharmacopoeia Apparatus 1 (baskets @100 rpm) or Apparatus. 2        (paddles @50 rpm) in 900 mL buffer releases not more than 10% of        the dose in about 3 minutes in a simulated saliva buffer at pH        6.8 and not less than about 60% of the dose in about 30 minutes        in an acidic buffer at pH 1.2.

These and other embodiments, advantages and features of the presentinvention become clear when detailed description and examples areprovided in subsequent sections.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the impact of the pore-former on the dissolution in0.1N HCl of taste-masked diphenhydramine hydrochloride beads of Example1;

FIG. 2 illustrates the dissolution profiles in 0.1N HCl ofdiphenhydramine chloride beads taste-masked with Ethylcellulose alone ofExample 2;

FIG. 3 illustrates the impact of the pore-former on the dissolutionprofiles in 0.1N HCl of taste-masked diphenhydramine hydrochloride beadsof Example 3;

FIG. 4 illustrates the dissolution profiles in 0.1N HCl ofdiphenhydramine hydrochloride beads taste-masked with polyvinyl acetatealone of Example 4; and

FIG. 5 illustrates the dissolution profiles in 0.1N HCl of Cetirizinedihydrochloride beads taste-masked with Ethylcellulose/calcium carbonateof Example 5.

DETAILED DESCRIPTION OF THE INVENTION

All documents cited are, in relevant part, incorporated herein byreference; the citation of any document is not to be construed as anadmission that it is prior art with respect to the present invention.

The term ‘drug’, ‘active’ or ‘active pharmaceutical ingredient’ as usedherein is meant to include the base, any pharmaceutically acceptablesalt, stereo-isomer and mixtures thereof. The term represents anytherapeutic agent indicated for oral administration. Examples oftherapeutic agents include, but are not limited to, NSAID analgesic,histamine H₁-receptor antagonist, histamine, H₂-receptor antagonist,5-HT₁ receptor agonist, 5-HT₃ receptor antagonist, antiepileptic drug,centrally acting adrenergic agonist, sleep-aid, leukotriene receptorantagonist, and a drug for the treatment of erectile dysfunctionrequiring taste-masking. Specific examples of the therapeutic agent usedin various embodiments of this invention include one or more from thegroup consisting of sumatriptan, electriptan, cetirizine, zafirlukast,montelukast, famotidine, ranitidine, tiagabine, fexofenadine,tizanidine, alphrazolum, ondansetron, granisetron, zolpidem, zaleplon,sildenafil, tadalafil and the like.

Unless indicated otherwise, all percentages and ratios are calculated byweight.

Unless indicated otherwise, all percentages and ratios are calculatedbased on the total composition.

Art aqueous or a pharmaceutically acceptable solvent medium may be usedfor preparing drug-containing core particles for taste-masking, viz.,beads by drug-layering onto inert sugar spheres in fluid-bed equipment.Examples of useful solvents include, but are not limited to, acetone,ethanol, isopropanol (IPA), water or a mixture thereof. The type offilm-forming binder that is used to bind the water-soluble drug to theinert sugar sphere is not critical but usually water-soluble,alcohol-soluble or acetone/water soluble binders are used. A binder suchas polyvinylpyrrolidone (PVP), polyethylene oxide, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), may be used atconcentrations of about 0.5 to 10% by weight based on the drug-layeredbeads. The drug substance may be present in this coating formulation insolution form or may be suspended at a solid content up to 35% by weightdepending on the viscosity of the coating formulation.

Crystals of a bitter API with a desired particle size range of fromabout 20 μm to 500 μm, more particularly from about 50 μm to 300 μm maybe taste-masked directly. Alternatively, microgranules containing milledor micronized drug may be produced by granulating in a high-sheargranulator the active and a suitable filler/diluent (if required) with apolymeric binder, which imparts resilient characteristics to the driedmicrogranules to resist attrition due to fluidization during fluid-bedcoating for taste-masking. The relative amounts of active, binder andoptional filler/diluent may vary considerably depending on theparticular active and the dosage form. Typically, microgranules preparedin accordance with this aspect of the invention will contain from about5% to about 95%, more particularly from about 20% to about 90% activeand up to about 15% binder with any optional filler/diluent beingpresent at from about 0% to about 90%, more particularly from about 20%to about 80%, by weight of the microgranules.

Examples of useful polymeric binders include, but are not limited to,hydroxypropylcellulose (Klucel® LF from Aqualon), modified starch (e.g.,Starch 1551 and Starch 1500, commercially available from National Starchand Colorcon, respectively), Kollidon® VA 64, poly (vinyl acetate-vinylpyrrolidone) from BASF, and hydroxypropyl methylcellulose with aviscosity of 100 cps or more (e.g., Methocel K100LV and Metolose K400commercially available from Dow Chemical and Shin Etsu Chemicals,respectively) alone or in combination with a widely used binder such asPVP (polyvinylpyrrolidone) or hydroxypropyl methylcellulose with aviscosity of 15 cps or less.

Examples of useful pharmaceutically acceptable fillers/diluents include,but are not limited to, mannitol, lactose, microcrystalline cellulose,potassium sulfate, calcium phosphate, modified starch and mixturesthereof.

The water-insoluble polymers suitable for taste-masking of bitter drugsby coating in fluid-bed equipment include, but are not limited to,ethylcellulose, cellulose acetate, cellulose acetate butyrate,methacrylate copolymers available under the trade name of ‘Eudragit’(type RL, RS and NE30D) and mixtures thereof. The gastrosoluble organicor inorganic pore-former is insoluble in water and saliva but is readilysoluble under acidic conditions. Examples of useful pore-formersinclude, but are not limited to, calcium carbonate, calcium phosphate,calcium saccharide, calcium succinate, calcium tartrate, ferric acetate,ferric hydroxide, ferric phosphate, magnesium carbonate, magnesiumcitrate, magnesium hydroxide, magnesium phosphate, and the like andmixtures thereof. The ratio of water-insoluble polymer to gastrosolubleorganic or inorganic pore-former for producing taste-masked particlesmay typically vary from about 95/5 to about 50/50, or in someembodiments from about 85/15 to 65/35, at a thickness of from about 5%to about 50%, more particularly from about 10% to about 30%, by weightof the coated bead.

The membranes described herein may also include one or moreplasticizers. Representative examples of plasticizers that may be usedto plasticize the membranes include triacetin, tributyl citrate,triethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, castoroil, dibutyl sebacate, acetylated monoglycerides and the like ormixtures thereof. The plasticizer may comprise typically about 10-30% orabout 5-15% based on the weight of dry polymer, depending on the use ofpolymer dispersions or solutions.

The ODT compositions described herein also include rapidly-dispersingmicrogranules. One or more sugar alcohols and/or saccharides and adisintegrant are granulated in a high shear granulator and dried in afluid bed equipment to produce rapidly-dispersing microgranules. Rapidlydispersing microgranules typically will contain disintegrant and sugaralcohol and/or saccharide at a ratio varying from about 90/10 to about99/1, or in some embodiments from about 90/10 to about 95/5 by weight.Examples of useful sugar alcohols include, without limitation, mannitol,sorbitol, xylitol, maltitol and mixtures thereof. Examples of usefulsaccharides include, but are not limited to, lactose, sucrose, maltoseand mixtures thereof. Each sugar alcohol or saccharide is characterizedby an average particle size of not more than about 30 μm. A disintegrantor a so-called super-disintegrant may be selected from the groupconsisting of crospovidone (crosslinked PVP), sodium starch glycolate,crosslinked sodium carboxymethyl cellulose, low substitutedhydroxypropylcellulose and mixtures thereof.

The ODT compositions may also include additional disintegrant separatefrom the rapidly dispersing microgranules. The additional disintegrantmay be present in the ODT formulation at up to about 10% based on thetablet weight.

It is to be understood that while the invention has been described inconjunction with specific embodiments thereof, that the descriptionabove as well as the examples that follow are intended to illustrate andnot limit the scope of the invention. Any modification within the scopeof the invention will be apparent to those skilled in the art to whichthe invention pertains.

An exemplary method of producing taste-masked microparticles (meanparticle size a about 100-400 μm) comprising one or more bitter activepharmaceutical ingredients) includes (i) preparing drug-containingparticles (crystals with a desired particle size range, microgranules,drug-layered or extruded/spheronized-heads) and (ii) membrane-coatingthe drug-containing particles for taste-masking. Crystals of a bitterAPI may be directly taste-masked if the drug substance with a desiredparticle size range of from about 20 μm to 500 μm, more particularlyfrom about 50 μm to 300 μm, is available. Drug-containing particles fortaste-masking may be produced by the other methods as well in accordancewith other aspects of the invention. The method of producingdrug-layered beads in one embodiment of the invention comprisesdissolving or suspending one or more active pharmaceutical ingredientsin a polymeric binder solution and layering onto inert particles such assugar spheres or Celphere (50-100 mesh or 150-300 μm) using a fluid-bedcoater equipped with a bottom-spray Wurster insert. Alternatively,another embodiment for producing resilient drug-containingmicrogranules, which undergo little or minimal attrition during membranecoating in fluid-bed equipment, includes granulating one or more activesand a filler or diluent (if needed) with a polymeric binder solution ina high-shear granulator. Yet another embodiment of the method ofproducing drug-containing beads involves granulating the active in ahigh-shear granulator as described above, followed by extrusion andspheronization of the wet mass using extrusion-spheronization equipment.

The method of producing taste-masked microparticles (crystals,microgranules, drug-layered or extruded/spheronized-beads) in accordancewith one aspect of the invention includes fluid-bed coating with amixture of a water-insoluble polymer such as ethylcellulose or polyvinylacetate and a gastrosoluble inorganic or organic pore-former such ascalcium carbonate or magnesium oxide at a ratio of about 50/50 to 95/05,more particularly from about 85/15 to 65/35, for a weight gain of fromabout 5% to about 50%, more particularly from about 10% to about 30%.

One specific embodiment of the invention comprises dissolvingwater-insoluble ethylcellulose in a 95/5 acetone/water with triethylcitrate (TEC) as the plasticizer (at about 10% of the weight ofethylcellulose) and suspending micronized calcium carbonate and coatingthe drug-cores (crystals, drug-layered beads, microgranules or pellets)in a fluid-bed coater equipped with a bottom-spray Wurster insert.

The invention also provides a method of manufacturing orallydisintegrating tablets, produced by mixing the taste-maskedmicroparticles, rapidly-dispersing microgranules and optionally otherexcipients (for example: flavor, color, sweetener, additionaldisintegrant, etc.) to form a blend and compressing the blend intoorally disintegrating tablets. In accordance with certain aspects of theinvention, the orally disintegrating tablets rapidly disintegrate oncontact with saliva in the buccal cavity leaving little or no aftertaste(good creamy mouth feel) and provide rapid, substantially-completerelease of the dose in the stomach, thereby enhancing the probability ofachieving bioequivalence to the reference product.

Rapidly-dispersing microgranules may be produced in accordance with themethod of manufacturing rapidly-dispersing microgranules disclosed inco-pending and commonly assigned U.S. patent application Ser. No.10/827,106, filed Apr. 19, 2004 and co-pending U.S. patent applicationSer. No. 11/213,266 filed Aug. 26, 2005. Rapidly dispersingmicrogranules with an average particle size of about 125-300 μm, moreparticularly from about 150-200 μm, comprising a disintegrant (forexample, Crospovidone XL-10) and a sugar alcohol or a saccharide or amixture thereof (for example, D-mannitol) having an average particlediameter of not more than about 30 μm, may be produced by granulatingwith only water in a high-shear granulator, wet milling and drying influid bed equipment. The taste-masked microparticles produced inaccordance with the present invention and rapidly-dispersiblemicrogranules may be blended with other pharmaceutically acceptableingredients and compressed into tablets, which rapidly disintegrate(e.g., typically in less than about 60 seconds) in the buccal cavitywith a smooth creamy mouth feel.

In yet another embodiment of the invention, a method to manufactureorally disintegrating tablets is provided. The orally disintegratingtablets may be formed by compressing in a tablet press equipped with anexternally lubricating system to pre-lubricate dies and punches and thetablet formulation otherwise being free of lubricant. The orallydisintegrating tablets thus produced typically exhibit sufficienthardness and sufficiently low friability and are suitable for packagingin HDPE bottles and push-through blister packs using conventionalequipment for storage, transportation and commercial distribution.

The pharmaceutical taste-masked multi-particulate composition inaccordance with certain embodiments provides acceptable taste-maskingwhen placed in the mouth until swallowed (target specification: not morethan about 10% of the dose released in about 3 minutes when tested fordissolution in simulating saliva fluid at pH about 7.0). If thecomposition is in the ODT (orally disintegrating tablet) form, thetablet typically will disintegrate on contact with saliva in the buccalcavity in about 60 seconds forming a smooth, easy-to swallow suspension,comprising taste-masked microparticles with acceptable aftertaste. Thesetaste-masked microparticles typically provide substantially-completerelease of the dose on entry into the stomach (target specification: notless than about 60%, more particularly not less than about 75% and inaccordance with certain embodiments not less than about 80% of the dosereleased in about 30 minutes when tested for dissolution in simulatedgastric fluid or 0.1N HCl at pH 1.2).

In accordance with one aspect of the invention, a method ofmanufacturing taste-masked microparticle composition of one or morebitter-tasting therapeutic agent(s), which exhibits acceptabletaste-masking when placed in the oral cavity and provides rapid-releaseof the dose on entry into the stomach, comprises the following steps:

-   -   (a) preparing a drug-containing core particle (crystal with a        particle size distribution of 20-500 μm, bead, pellet or        granule) by (i) drug-layering on an inert particle (e.g., 50-100        mesh sugar sphere or cellulose sphere (e.g., Celphere® CP-203        available from Asahi Kasei Chemicals Corporation)) from a        solution/suspension comprising a polymeric binder and the drug        in a fluid-bed coater and coating with a seal-coat (e.g.,        Opadry® Clear), or (ii) granulating the drug and a        filler/diluent such as lactose, mannitol or microcrystalline        cellulose with a polymeric binder in a high-shear granulator,        or (iii) granulating as above, followed by extrusion and        spheronization; and    -   (b) coating the core particles with a solution/suspension of a        water-insoluble functional polymer and a gastrosoluble organic        or inorganic pore-former (for example, ethylcellulose/calcium        carbonate at a ratio ranging from about 50/50 to 95/5, more        particularly from about 60/40 to 90/10 and in certain        embodiments from about 65/35 to 85/15, for a weight gain of        about 5% to 50%, more particularly from about 10% to 45% and in        certain embodiments from about 15% to 30%) to produce        effectively taste-masked microparticles with a desired particle        size distribution (an average particle size of not more than        about 400 μm, more particularly not more than about 300 nm).

In accordance with another aspect of the invention, the method ofmanufacturing orally disintegrating tablets, which disintegrate oncontact with saliva in the buccal cavity forming a smooth, easy-toswallow suspension with acceptable aftertaste, comprising taste-maskedmicroparticles, which rapidly release the dose on entry into thestomach, comprises the following steps:

-   -   (a) preparing a drug-containing core particle (crystal with a        particle size distribution of 20-500 μm, bead, pellet or        granule) by (i) drug-layering on an inert particle (e.g., 50-100        mesh sugar sphere or cellulose sphere, e.g., Celphere® CP-203)        from a solution/suspension comprising a polymeric binder and the        drug in a fluid-bed coater and applying a seal-coat (e.g.,        Opadry® Clear), or (ii) granulating the drug and a        diluent/filler such as lactose, mannitol or microcrystalline        cellulose with a polymeric binder in a high-shear granulator,        or (iii) granulating as above, followed by extrusion and        spheronization;

(b) coating core particles with a solution/suspension of awater-insoluble functional polymer and a gastrosoluble organic orinorganic pore-former (e.g., ethylcellulose/calcium carbonate at a ratioranging from about 50/50 to 95/5) to produce effectively taste-maskedmicroparticles with a desired particle size distribution (an averageparticle size of not more than about 400 μm, more particularly not morethan about 300 μm);

-   -   (c) granulating a sugar alcohol or a saccharide, or a        combination thereof, each of which has an average particle        diameter of not more than about 30 μm, with a disintegrant such        as Crospovidone using water or an alcohol-water mixture in a        typical granulator and drying in fluid-bed equipment to produce        rapidly-dispersing microgranules with an average particle size        of not more than about 400 μm (typically the average particle        size will be in the range of about 100-300 μm);    -   (d) blending taste-masked microparticles of step (b) with        rapidly-dispersing microgranules of step (c) at a ratio of from        about ⅙ to ½, more particularly'from about ¼ to ⅓, and        optionally other acceptable ingredients such as a flavoring        agent, a coloring agent, and a sweetener in sufficient        quantities typically up to about 1%, more particularly about        0.5% and additional disintegrant up to about 5%, more        particularly about 4% based on the tablet weight; and    -   (e) compressing into tablets using a conventional rotary tablet        press equipped with an external lubrication system to        pre-lubricate the dies and punches.

In vitro dissolution testing: The taste-masking property of thetaste-masked microparticles and the orally disintegrating tablets may beevaluated in the mouth by determining the percentage of drug-release (arelease of not more than about 10% of the dose in about 3 minutes isconsidered acceptable) when tested for dissolution using USP Apparatus 1(baskets @100 rpm) or 2 (paddles @50 rpm) in 900 mL of saliva-simulatingfluid (at a pH of about 7.0). Further, the rapid-release property in thestomach of the taste-masked microparticles and the orally disintegratingtablets may be evaluated by determining the percentage of drug-release(a release of not less than about 60% of the dose in about 30 minutes isconsidered acceptable) when tested for dissolution using USP Apparatus 1(baskets @100 rpm) or Apparatus 2 (paddles @50 rpm) in 900 mL of 0.1NHCl (at pH 1.2).

In accordance with certain embodiments of the invention, thetaste-masked pharmaceutical composition is in the form of a tablet andexhibits low friability in order to be suitable for packaging blistersand bottles for storage, transportation and commercial distribution.Friability can be determined in accordance with the standardpharmaceutical test methods that are well known to those skilled in theart. Friability for tablets produced in accordance with certain aspectsof the invention will have a friability of not more than about 1% and inaccordance with certain embodiments not more than about 0.5%.

The following non-limiting examples illustrate the taste-maskedmicroparticle composition or an orally disintegrating tablet dosage formcomprising one or more therapeutic agent(s) requiring taste-masking,manufactured in accordance with the invention, which exhibits acceptabletaste-masking when placed in the mouth and substantially complete,rapid-release of the dose on entry into the stomach. All percentages andratios are by weight unless indicated otherwise.

EXAMPLE 1

Drug-layered Diphenhydramine hydrochloride Beads (drug load: 15%)Diphenhydramine hydrochloride (375 g) was slowly added to an aqueoussolution of 41.8 g polyvinylpyrrolidone (binder) and 1667 g of purifiedwater and mixed well. 60-80 mesh sugar spheres (1470 g) were coated withthe drug-layering formulation in a Glatt GPCG 3. The drug containingpellets were dried, and a seal coat of Opadry Clear for a weight gain of4% was applied on the drug-layered beads.

Taste-masked Beads with Ethylcellulose (EC-IT/Calcium Carbonate: 1000 gof drug-layered beads produced above were coated in the Glatt GPCG 3with a membrane comprising 227.3 g of EC-10, 22.7 g of Myvacet 9-45(diacetylated monoglyceride) and 68.2 g of calcium carbonatedissolved/suspended in 3916.6 g of 95/5 acetone/water. The coated beadswere dried in the Glatt GPCG-3. The dissolution profiles in 0.1N HCl ofthe beads with a membrane thickness of up to 20% by weight are shown inFIG. 1.

EXAMPLE 2

(Reference): Taste-masked Beads with Ethylcellulose (EC-10) alone: IRbeads were coated with a solution of EC-10/Myvacet 9-45 at a ratio of90/10 dissolved in 95/5 acetone/water for a weight gain of up to 20%.The coated beads were dried in the Glatt GPCG-3. The taste-masked beadscoated at 20% typically release less than about 10% in 5 minutes whendissolution tested using the USP Apparatus 2 (paddles @50 rpm) in aphosphate buffer at pH 6.8. The dissolution profiles in 0.1N HCl of thebeads with a membrane thickness of up to 20% by weight are shown in FIG.2 suggesting that both taste-masking and rapid release can be achievedwhen coated with ethylcellulose alone from a solvent mixture althoughthe dissolution profiles from the beads thus coated at acceptabletaste-masking levels do not meet the desired dissolution profile for acorresponding immediate release product.

Rapidly Dispersing Microgranules: The rapidly dispersing microgranulesmay comprise a sugar alcohol such as mannitol and/or a saccharide suchas lactose and a disintegrant such as crosslinked povidone(Crospovidone). Typically, mannitol and crospovidone with an averageparticle size of less than 30 μm are granulated at a ratio of about 95/5in a high shear granulator such as GMX 600 and dried in a fluid-beddrier such as Glatt GPCG 200 to produce rapidly dispersingmicrogranules.

ODT Diphenhydramine Hydrochloride: 208 parts of taste-masked beads at20% coating and 624 parts of the mix (93.38%, rapidly-dispersingmicrogranules, 5.91% crospovidone, 0.35% orange flavor, and 0.35%Aspartame) would be blended together and compressed into 832 mg tabletscontaining 25 mg of diphenhydramine hydrochloride with an averagehardness of >5 kP. The tablets would release not more than about 10% inabout 5 minutes when dissolution tested using the USP Apparatus 2(paddles @50 rpm) at pH 6.8. In contrast, not less than about 75% of theactive would be released in about 45 minutes when dissolution tested in900 mL 0.1N HCl using USP Apparatus 2 (paddles @50 rpm).

EXAMPLE 3

Taste-masked Beads with Polyvinyl acetate/Calcium Carbonate: 1000 g ofdrug-layered beads were coated in the Glatt GPCG-3 with a membranecomprising 550 g of Kollicoat SR30D (30% polyvinyl acetate aqueousdispersion), 5.8 g of Myvacet, 49.5 g of micronized calcium carbonateand 30 g of magnesium stearate dissolved/suspended in 2760.9 g ofethanol (final ratio of ethanol/water: 87/13). The coated beads weredried in the Glatt GPCG-3. The dissolution profiles in 0.1N HCl of thebeads with a membrane thickness of up to 20% by weight are shown in FIG.3.

EXAMPLE 4

(Reference): Taste-masked Beads with Polyvinyl acetate alone: IR beadsproduced in Example 1 were coated with a solution/suspension ofpolyvinyl acetate (Kolloidon SR30D) with Myvacet 9-45/talc at 2.9/11.5dissolved in 87/13 ethanol/water for a weight gain of up to 20%. Thecoated beads were dried in the Glatt GPCG-3. The taste-masked beadscoated at 20% typically release less than about 10% in 5 minutes whendissolution tested using the USP Apparatus 2 (paddles @50 rpm) in aphosphate buffer at pH 6.8. The dissolution profiles in 0.1N HCl of thebeads with a membrane thickness of up to 20% by weight are shown in FIG.4.

Based on these observations as well as the observations in Example 1, itis amply clear that both effective taste-masking and rapid dissolutionin acidic buffers can be achieved when active-containing cores arecoated with a water-insoluble polymer (e.g., ethylcellulose or polyvinylacetate) alone from a solvent mixture although the dissolution profilesfrom the beads thus coated at acceptable taste-masking levels may notprovide the dissolution profiles corresponding to an immediate releaseformulation.

EXAMPLE 5

Drug-layered Cetirizine dihydrochloride Beads (drug load: 8.4%):Cetirizine dihydrochloride (180 g) was slowly added to an aqueoussolution of 15.7 g polyvinylpyrrolidone (binder) and 782.8 g of purifiedwater and mixed well. 60-80 mesh sugar spheres (1900 g) were coated withthe drug-layering formulation in a Glatt GPCG 3. The drug containingpellets were dried, and a seal coat of Opadry Clear for a weight gain of2% was applied on the drug-layered beads.

Taste-masked Beads with Ethylcellulose/Calcium Carbonate: IR beadsproduced above were coated with a solution/suspension of EC-10/Myvacet9-45/calcium carbonate at a ratio of 71.5/7.1/21.4 in 2620:8 g of 95/5acetone/water for a weight gain of up to 20%. The coated beads weredried in the Glatt GPCG-3. The taste-masked beads coated at 20% released13% in 5 minutes when dissolution tested using the USP Apparatus 2(paddles @50 rpm) in a phosphate buffer at pH 6.8. The dissolutionprofiles in 0.1N HCl of the beads with a membrane thickness of up to 20%by weight are shown in FIG. 5.

ODT Cetirizine dihydrochloride: 744 g of taste-masked beads at 20%coating, 1734 g of rapidly-dispersing microgranules, 110 g ofcrospovidone, 13 g orange flavor, and 13 g of Aspartame) would beblended together and compressed into 520 mg tablets containing 10 mg ofcetirizine dihydrochloride with an average hardness of >5 kP. Thetablets would release not more than 10% in about 5 minutes whendissolution tested using the USP Apparatus 2 (paddles 50 rpm) at pH 6.8.In contrast, not less than 75% of the active would be released in about45 minutes when dissolution tested in 900 mL 0.1N HCl using USPApparatus 2 (paddles @50 rpm).

EXAMPLE 6

Taste-masked microparticles of Sumatriptan succinate (drug load:approximately 63% of sumatriptan succinate): Sumatriptan succinate (90%)was granulated with an aqueous solution (25% solids) of hydroxypropylmethylcellulose (Methocel K100LV at 10% by weight of the drug) in ahigh-shear granulator and tray-dried in a convection oven. The resilientgranules with an average particle size of about 200 pm would be coatedwith a 95/5 acetone/water solution/suspension (10% solids) containing68/7/25 Ethocel (EC-10)/TEC/calcium carbonate in a fluid-bed coater fora weight gain of up to 30%. The coated granules coated 30% would releaseless than about 10% active in 5 minutes at pH 6.8. Yet the taste-maskedbeads would release not less than about 75% in 45 minutes whendissolution tested in 0.1N HCl.

Sumatriptan Succinate ODT, 100 mg (as sumatriptan): 2,160 g oftaste-masked microparticles and 3,720 g of rapidly-dispersingmicrogranules would be blended with crospovidone (72 g), a strawberryflavor (18 g), Aspartame (30 g) and compressed into tablets with anaverage weight of 1,500 mg and average hardness of >7 kP to demonstraterobustness of the manufacturing (taste-masking and tableting) processand meeting drug-release specifications when dissolution tested insimulated saliva and 0.1N HCl.

Changes may be made by persons skilled in the art in the composition andthe manufacturing procedures as described herein or in the steps or thesequence of steps of the method of manufacture described therein withoutdeparting from the spirit and scope of the invention as described above.

1. A pharmaceutical composition comprising: (1) a plurality oftaste-masked particles, wherein each taste-masked particle comprises:(a) a drug-containing core particle; (b) a taste-masking membranedisposed on said drug-containing core particle comprising a combinationof (i) a water-insoluble polymer and (ii) a gastrosoluble inorganic ororganic pore-former at a ratio ranging from about 95/5 to about 50/50,wherein the water-insoluble polymer is selected from the groupconsisting of ethylcellulose, polyvinyl acetate, cellulose acetate,cellulose acetate phthalate, cellulose acetate butyrate, methacrylatecopolymers and combinations thereof, and the gastrosoluble organic orinorganic pore-former is selected from the group consisting of calciumcarbonate, calcium phosphate, calcium saccharide, calcium succinate,calcium tartrate, ferric acetate, ferric hydroxide, ferric phosphate,magnesium carbonate, magnesium citrate, magnesium hydroxide, magnesiumoxide, magnesium phosphate and mixtures thereof, and the compositionreleases greater than or equal to about 60% of the total amount of drugin 30 minutes when tested for dissolution using United StatesPharmacopoeia Apparatus 2 using paddles—at 50 rpm in 900 mL of pH 1.2buffer; and (2) a plurality of rapidly-dispersing microgranules havingan average particle size of not more than about 400 μm comprising (i) adisintegrant and (ii) a sugar alcohol or a saccharide or a combinationthereof, wherein each of said disintegrant and sugar alcohol orsaccharide is present in the form of particles having an averageparticle diameter of not more than about 30 μm, wherein the ratio ofsaid sugar alcohol, said saccharide or combination thereof to saiddisintegrant in the rapidly-dispersing microgranules is from about 90/10to about 99/1; wherein the pharmaceutical composition is an orallydisintegrating tablet.
 2. The pharmaceutical composition of claim 1,wherein said taste-masked particles release less than or equal to about10% of the total amount of drug in about 3 minutes when dissolutiontested in simulated saliva fluid at about pH 6.8.
 3. The pharmaceuticalcomposition of claim 1, comprising one or more drug(s) present in atherapeutically effective amount.
 4. The pharmaceutical composition ofclaim 1, wherein the drug is selected from the group consisting ofdiphenhydramine, ranitidine, famotidine, cetirizine, fexofenadine,sumatriptan, eletriptan, zolmitriptan, ondansetron, granisetron,tiagabine, tizanidine, zolpidem, zaleplon, zafirlukast, montelukast,sildenafil, tadalafil, pharmaceutically acceptable salts thereof, andcombinations thereof.
 5. The pharmaceutical composition of claim 1,wherein the drug-containing particle comprises a drug-layered beadcomprising an inert particle coated with one or more pharmaceuticallyacceptable drug(s).
 6. The pharmaceutical composition of claim 1,wherein the drug-containing particle comprises a microgranule or anextruded and spheronized pellet comprising: 1) one or morepharmaceutically acceptable drug(s), 2) a polymeric binder, and 3) afiller and/or diluent.
 7. The pharmaceutical composition of claim 1,wherein said drug requires taste-masking.
 8. The pharmaceuticalcomposition of claim 1, wherein the membrane thickness ranges from about5% to 50% by weight of the coated particle.
 9. The pharmaceuticalcomposition of claim 1, wherein the water-insoluble polymer comprisesethylcellulose and the gastrosoluble pore former comprises calciumcarbonate.
 10. The pharmaceutical composition of claim 1, wherein theratio of rapidly-dispersing microgranules to taste-masked particlesranges from about 6/1 to about 2/1.
 11. The pharmaceutical compositionof claim 1, wherein the rapidly-dispersing microgranules comprise adisintegrant selected from the group consisting of crosslinkedpolyvinylpyrrolidone, sodium starch glycolate, crosslinked sodiumcarboxymethylcellulose, low-substituted hydroxypropylcellulose andmixtures thereof.
 12. The pharmaceutical composition of claim 1, whereinthe average particle size of the drug-containing core particle is lessthan or equal to about 400 μm.
 13. The pharmaceutical composition ofclaim 1, wherein said orally disintegrating tablet has a friability ofless than or equal to about 1%.
 14. The pharmaceutical composition ofclaim 1, wherein said orally disintegrating tablet disintegrates oncontact with saliva in an oral cavity within approximately 60 seconds.15. The pharmaceutical composition of claim 1, wherein the rapidlydispersing microgranules comprise a sugar alcohol or a saccharideselected from the group consisting of mannitol, xylitol, sorbitol,maltol, maltitol, lactose, sucrose, maltose, and combinations thereof.16. The pharmaceutical composition of claim 1, wherein the gastrosolubleorganic or inorganic pore former is a salt.
 17. The pharmaceuticalcomposition of claim 1, wherein the pharmaceutical composition exhibitsacceptable taste-masking when placed in the oral cavity for 60 seconds.18. The pharmaceutical composition of claim 1, wherein the rapidlydispersing microgranules have an average particle size of less than orequal to about 300 μm.
 19. A method of manufacturing a pharmaceuticalcomposition comprising: (a) preparing core particles comprising a drug;(b) coating the core particles by applying a membrane comprising amixture of (i) water-insoluble polymer and (ii) a gastrosoluble organicor inorganic pore former present at a ratio of from about 95/5 to about50/50, wherein the water-insoluble polymer is selected from the groupconsisting of ethyl cellulose, polyvinyl acetate, cellulose acetate,cellulose acetate phthalate, cellulose acetate butyrate, methacrylatecopolymers and combinations thereof, and the gastrosoluble organic orinorganic pore-former is selected from the group consisting of calciumcarbonate, calcium phosphate, calcium saccharide, calcium succinate,calcium tartrate, ferric acetate, ferric hydroxide, ferric phosphate,magnesium carbonate, magnesium citrate, magnesium hydroxide, magnesiumoxide, magnesium phosphate and mixtures thereof; (c) granulatingparticles of a sugar alcohol or a saccharide, or a combination thereof,each particle of sugar alcohol or saccharide having an average particlediameter of not more than 30 μm, with a disintegrant having an averageparticle diameter of not more than 30 μm to produce rapidly-dispersingmicrogranules with an average particle size of not more than about 400μm, wherein the ratio of said sugar alcohol, said saccharide orcombination thereof to said disintegrant in the rapidly-dispersingmicrogranules is from about 90/10 to about 99/1; (d) blending themembrane coated particles of step (b) with the rapidly-dispersingmicrogranules of step (c) at a ratio of about ⅙ to about ½; and (e)compressing the blend of step (d) into orally disintegrating tablets.20. The method of claim 19, wherein the water-insoluble polymercomprises ethyl cellulose and the gastrosoluble organic or inorganicpore former comprises calcium carbonate.
 21. The method of claim 19,wherein said step of compressing (e) comprises utilizing a conventionalrotary tablet press equipped with an external lubrication system topre-lubricate the dies and punches.
 22. The method of claim 19, whereinthe orally disintegrating tablets, when tested for dissolution usingUnited States Pharmacopoeia Apparatus 2 using paddles at 50 rpm in 900mL buffer, release less than or equal to about 10% of the total amountof the drug in about 3 minutes in a simulated saliva buffer at pH 6.8and greater than or equal to about 60% of the total amount of the drugin about 30 minutes in an acidic buffer at pH 1.2.
 23. The method ofclaim 19, wherein said rapidly-dispersing microgranules have an averageparticle size of not more than 300 μm.
 24. The method of claim 19,wherein the membrane is present in an amount of from about 5% to about50% based on the total weight of the coated particles.
 25. The method ofclaim 19, wherein the pharmaceutical composition exhibits acceptabletaste-masking when the composition is placed in the oral cavity for 60seconds.
 26. The method of claim 19, wherein the pharmaceuticalcomposition releases greater than or equal to about 60% of the totalamount of the drug in 30 minutes when tested for dissolution usingUnited States Pharmacopeia Apparatus 2 using paddles at 50 rpm in 900 mLof pH 1.2 buffer.